The present invention relates to methods for producing isochromanone compounds useful as raw materials for drugs and agricultural chemicals and to methods for producing intermediate compounds for the production of isochromanone compounds. More particularly, the present invention relates to (1) methods for producing isochromanone compounds from o-xylene compounds as starting compounds through xcex1-halogeno-o-xylene derivatives, xcex1-cyano-o-xylene derivatives, and xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene derivatives, and (2) methods for producing isochromanone compounds from o-xylene compounds as starting compounds through xcex1,xcex1xe2x80x2-dihalogeno-o-xylene derivatives, xcex1,xcex1xe2x80x2-dihydroxy-o-xylene derivatives, xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene derivatives and xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene derivatives, and (3) methods for producing these intermediates for the production of isochromanone compounds.
(1) As a general method for producing xcex1-halogeno-o-xylene compounds, various methods have heretofore been known. For example, in the case of xcex1-chloro-o-xylene, there have been known a reaction of o-xylene as a starting compound with N-halogenated succinimide and a reaction of o-xylene as a starting compound with sulfuryl chloride or chlorine in the presence of azobisisobutyronitrile (AIBN).
Also, a method for selectively producing of xcex1-chloro-o-xylene by reaction of 2-methylbenzyl alcohol (xcex1-hydroxy-o-xylene) with thionyl chloride has been known (J. Am. Chem. Soc., 62, 2295 (1940)).
Of these methods, the method in which o-xylene and chlorine are reacted tends to give di- or tri-substituted perchlorides and it is difficult to obtain only xcex1-chloro-o-xylene selectively.
The method in which 2-methylbenzyl alcohol and thionyl chloride are reacted by-produces highly toxic sulfurous acid gas and hence is undesirable as a commercial method.
Thus, conventional production methods for xcex1-halogeno-o-xylene compounds produce highly toxic by-products or the target product, xcex1-halogeno-o-xylene, has low selectivity so that they are not always satisfactory methods for practicing on an industrial scale.
(2) Production methods for xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compounds include a method in which xcex1,xcex1xe2x80x2-dibromo-o-xylene is heated in the presence of sodium hydroxide to obtain xcex1,xcex1xe2x80x2-dihydroxy-o-xylene (Ber., 17, 123 (1884)). xcex1,xcex1xe2x80x2-Dihydroxy-o-xylene is under alkaline condition and when heated, an intermediate xcex1-hydroxy-xcex1xe2x80x2-halogeno-o-xylene undergoes intramolecular dehalogenohydrogenation to produce phthalan of formula (XI) and the yield of objective xcex1,xcex1xe2x80x2-dihydroxy-o-xylene decreases so that the method is not suitable for industrial application. 
Similarly, a method has been reported in which xcex1,xcex1xe2x80x2-dibromo-o-xylene is hydrolyzed in the presence of potassium hydroxide to obtain xcex1,xcex1xe2x80x2-dihydroxy-o-xylene (Ann. Chim. Phys., [6]6, 106 (1885)). Similarly, phthalan is produced and is not advantageous for industrial application.
Further, a method in which o-phthaloyl dichloride is converted to xcex1,xcex1xe2x80x2-dihydroxy-o-xylene with sodium amalgam (Ber., 12, 646 (1879)), a method in which phthalic anhydride or o-phthaloyl dichloride is reduced with lithium aluminum hydride (LiAlH4)to synthesize xcex1,xcex1xe2x80x2-dihydroxy-o-xylene (Nystrom et al., J. Am. Chem. Soc., 69, 1197-9 (1947)), a method in which o-phthaloyl dichloride is reacted with sodium borohydride (NaBH4) in dioxane to obtain xcex1,xcex1xe2x80x2-dihydroxy-o-xylene (Chaikin et al., J. Am. Chem. Soc., 71, 122-5 (1949)) are known. In each case, starting compounds are not available industrially so that they are not industrially advantageous.
Further, there is disclosed a method for producing a, xcex1xe2x80x2-dihydroxy-o-xylene in which xcex1,xcex1xe2x80x2-dichloro-o-xylene is reacted with water in the presence of an alkali metal formate or alkaline earth metal formate (JP-A-64-26528). Addition of formate necessitates disposal of formic acid after ultimately recovering xcex1,xcex1xe2x80x2-dihydroxy-o-xylene. That is, there occurs mixing of formic acid, which is a BOD source, into wastewater so that treatment of wastewater becomes necessary, making the process complicated.
(3) There have been few report on the production method for xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes. An example of reports is Research Disclosure (RD) 409066, p.581-584. This discloses synthesis of xcex1-chloro-xcex1xe2x80x2-cyano-o-xylene by reacting xcex1-cyano-o-xylene with sulfuryl chloride in fluorobenzene as a solvent. However, the method uses sulfuryl chloride, which is expensive, as a chlorinating agent and is unsatisfactory as an industrial method.
(4) The production method for xcex1-halogeno-xcex1xe2x80x2-hydroxy-xylenes is reported in J. Org. Chem., 57, 4074-4079 (1992). In this production method, xcex1,xcex1xe2x80x2-dihydroxy-xylene is reacted with thionyl chloride using benzene as a solvent and pyridine as a catalyst. However, this method requires overnight reaction time and yield of the reaction is as low as 59.5% so that it is not advantageous for industrial application.
(5) xcex1-Carboxy-xcex1xe2x80x2-hydroxy-xylenes and salts thereof are industrially useful compounds. However, there are few industrial production methods.
On the production method for xcex1-carboxy-xcex1xe2x80x2-hydroxy-xylenes and salts thereof, JP-A-9-67364 describes that trial to synthesize them through xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene by reacting xcex1,xcex1xe2x80x2-dihalogeno-o-xylene with carbon monoxide and water in the presence of a catalyst such as palladium failed since xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene was not synthesized.
Regarding xcex1,xcex1xe2x80x2-dihalogeno-m-xylene or xcex1,xcex1xe2x80x2-dihalogeno-p-xylene, it is considered that xcex1-carboxy-xcex1xe2x80x2-hydroxy-xylenes can be synthesized therefrom similarly to the method described in JP-A-9-67364. However, use of expensive catalysts is required so that such a method is not an industrially advantageous method.
(6) Regarding 3-isochromanone, there is a report that it can be synthesized by reacting o-bromomethylbenzyl alcohol (xcex1-bromo-o-xylene) with carbon monoxide in the presence of palladium complex catalyst (J. Am. Chem. Soc., 102, 4191 (1908)). However, use of expensive catalysts does not make the method industrially advantageous.
Further, Research Disclosure (RD) 409066, p.581-584 discloses a method in which 3-isochromanone is produced using xcex1-chloro-xcex1xe2x80x2-cyano-o-xylenes as raw material and large excess sulfuric acid and tetrabutylammonium bromide. This method uses a large amount of sulfuric acid and hence produces a large amount of wastewater, thus raising the problems of imposing a large load on the environment and low yields.
Further, as another method, a method has been known in which xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes are subjected to alkali hydrolysis in an aqueous solution of sodium hydroxide or potassium hydroxide, and the reaction mixture is rendered acidic by addition of acid to cyclize them. This method requires two reaction processes, i.e., the alkali hydrolysis of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes (hydrolysis reaction step) and then acidification with acid (cyclizing step), resulting in that yield is too low for the method to be adopted industrially.
A main object of the present invention is to provide an industrially advantageous production method that can efficiently give 3-isochromanone compounds from o-xylene compounds as raw materials.
More particularly, an object of the present invention is to use o-xylene compounds as raw materials and provide:
(1) an industrially advantageous production method for isochromanone compounds through xcex1-halogeno-o-xylene derivatives, xcex1-cyano-o-xylene derivatives, and xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene derivatives.
Also, an object of the present invention is to use o-xylene compounds as raw materials and provide: (2) an industrially advantageous production method for isochromanone compounds through xcex1,xcex1xe2x80x2-dihalogeno-o-xylene derivatives, xcex1,xcex1xe2x80x2-dihydroxy-o-xylene derivatives, and xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene derivatives, or xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene derivatives.
Further, other object of the present invention is to provide novel production method for xcex1-chloro-o-xylene compounds, xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compounds, xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compounds, and xcex1-chloro-xcex1xe2x80x2-cyano-o-xylene compounds, which are intermediates for the production methods for isochromanone compounds in (1) and (2) above.
The present invention relates to a production method for the following isochromanone compounds, a production method for xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compounds, a production method for xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compounds, a production method for xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compounds, and a production method for xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compounds.
(1) A method for producing isochromanone compound of formula (V) 
(wherein R1 and R2 independently of each other represent hydrogen atom or an alkyl group, R3 represents hydrogen atom, halogen atom, an alkoxy group, a hydroxyalkyl group having 2 or more carbon atoms, or a carboxyl group, and n is an integer of 0 to 4, provided that when n is 2 or more, (R3)s may be the same or different), which comprises the steps of:
subjecting an o-xylene compound of formula (I) 
xe2x80x83(wherein the symbols have the same meanings as defined above) to halogenation reaction in gas phase or liquid phase to prepare an xcex1-halogeno-o-xylene compound of formula (II) 
(wherein X represents a halogen atom, and other symbols have the same meanings as defined above);
reacting the compound of formula (II) above with hydrogen cyanide or salts thereof to prepare an xcex1-cyano-o-xylene compound of formula (III) 
xe2x80x83(wherein the symbols have the same meanings as defined above);
reacting the compound of formula (III) with halogen to prepare an xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound of formula (IV) 
xe2x80x83(wherein the symbols have the same meanings as defined above); and
hydrolyzing the compound of formula (IV) in water or water containing a protic polar solvent under acidic condition.
(2) A method for producing isochromanone compound of formula (V) 
(wherein the symbols have the same meanings as defined above), which comprises the step of:
hydrolyzing an xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene of formula (IV) 
(wherein the symbols have the same meanings as defined above) in water or water containing a protic polar solvent under acidic condition.
(3) The method for producing isochromanone compound as described in (2) above, wherein the protic polar solvent is lower alcohol.
(4) The method for producing isochromanone compound as described in (2) above, wherein an inorganic acid and/or a metal chloride are added and hydrolysis reaction is carried out.
(5) The method for producing isochromanone compound as described in (4) above, wherein the metal chloride is aluminum chloride or zinc chloride.
(6) The method for producing isochromanone compound as described in (4) above, wherein addition amount of the inorganic acid and/or metal chloride is 0.1 to 5 equivalents per xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound.
(7) The method for producing isochromanone compound as described in (2) above, wherein the hydrolysis reaction is carried out under heating conditions at 70 to 200xc2x0 C.
(8) The method for producing isochromanone compound as described in (2) above, wherein the hydrolysis reaction is carried out under pressurized conditions at atmospheric pressure to 20 kg/cm2.
(9) The method for producing isochromanone compound as described in (2) above, wherein the xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound of formula (IV) is xcex1-chloro-xcex1xe2x80x2-cyano-o-xylene and the isochromanone compound of formula (V) is 3-isochromanone.
(10) A method for producing xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound of formula (IV) 
(wherein the symbols have the same meanings as defined in (1) above) comprising the step of:
reacting an xcex1-cyano-o-xylene compound of formula (III) 
xe2x80x83(wherein the symbols have the same meanings as defined above) with halogen.
(11) The method for producing xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound as described in (10) above, wherein the xcex1-cyano-o-xylene compound is diluted with an organic solvent and reaction is carried out in liquid phase.
(12) The method for producing xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound as described in (10) above, wherein the reaction is carried out in the presence of a radical initiator or under irradiation of ultraviolet rays.
(13) The method for producing xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound as described in (10) above, wherein the xcex1-cyano-o-xylene compound is vaporized and the reaction is carried out in gas phase.
(14) The method for producing xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound as described in (10) above, wherein the xcex1-cyano-o-xylene compound is xcex1-cyano-o-xylene and the xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound is xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene.
(15) A method for producing isochromanone compound of formula (V) 
(wherein R1 and R2 independently of each other represent hydrogen atom or an alkyl group, R3 represents hydrogen atom, halogen atom, an alkoxy group, a hydroxyalkyl group having 2 or more carbon atoms, or a carboxyl group, and n is an integer of 0 to 4, provided that when n is 2 or more, (R3)s may be the same or different), which comprises the steps of:
subjecting an o-xylene compound of formula (I) 
xe2x80x83(wherein the symbols have the same meanings as defined above) to halogenation reaction in gas phase or liquid phase to prepare an xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound of formula (VI) 
(wherein X represents a halogen atom, and other symbols have the same meanings as defined above);
heating the compound of (VI) in the presence of water at pH 8 or lower to prepare an xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound of formula of formula (VII) 
xe2x80x83(wherein the symbols have the same meanings as defined above);
reacting the compound of formula (VII) with hydrogen halide to prepare an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (VIII) 
xe2x80x83(wherein the symbols have the same meanings as defined above);
reacting the compound of formula (VIII) with hydrogen cyanide or salts thereof to prepare an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (IX) 
xe2x80x83(wherein the symbols have the same meanings as defined above); and
acid hydrolyzing the compound of formula (IX).
(16) A method for producing an isochromanone compound of formula (V) 
(wherein the symbols have the same meanings as defined in (15) above), comprising the step of:
acid hydrolyzing a compound of formula (IX) 
xe2x80x83(wherein the symbols have the same meanings as defined above).
(17) The method for producing an isochromanone compound as described in (16) above, wherein an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (IX) 
(wherein the symbols have the same meanings as defined in (15) above) obtained by reacting a compound of formula (VIII) 
(wherein the symbols have the same meanings as defined above) with hydrogen cyanide or salts thereof is used.
(18) A method for producing an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (IX) 
(wherein the symbols have the same meanings as defined in (15) above), comprising the step of:
reacting an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (VIII) 
xe2x80x83(wherein the symbols have the same meanings as defined above) with hydrogen cyanide or salts thereof.
(19) The method for producing an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (18) above, wherein an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (VIII) obtained by reacting a compound of formula (VII) 
(wherein the symbols have the same meanings as defined above) with hydrogen halide is used.
(20) The method for producing an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (18) above, wherein hydrogen cyanide or salts thereof are reacted at a pH in the range of 4 to 10.
(21) The method for producing an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (18) above, wherein hydrogen cyanide or salts thereof are reacted by addition of a phase transfer catalyst.
(22) The method for producing an xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (18) above, wherein the xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound is xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene.
(23) A method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (VIII) 
(wherein the symbols have the same meanings as defined in (15) above), comprising the step of reacting a xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound of formula (VII) 
(wherein the symbols have the same meanings as defined above) with hydrogen halide.
(24) The method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (23) above, wherein the reaction is carried out in an aqueous solution.
(25) The method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (24) above, wherein a hydrophobic organic solvent is used together.
(26) The method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (24) above, wherein water is used 5 to 15 folds by mole based on the xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound.
(27) The method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (23) above, wherein for the reaction, the hydrogen halide is used 1.5 to 3 folds by mole based on the xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound.
(28) The method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (23) above, wherein the hydrogen halide is hydrogen chloride.
(29) The method for producing an xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (23) above, wherein the xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound of formula (VII) is xcex1,xcex1xe2x80x2-dihydroxy-o-xylene and the xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (VIII) is xcex1-chloro-xcex1xe2x80x2-hydroxy-o-xylene.
(30) A method for producing an xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound of formula (VII) 
(wherein the symbols have the same meanings as defined in (15) above), comprising the step of:
heating an xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound of formula (VI) 
xe2x80x83(wherein the symbols have the same meanings as defined above) at pH 8 or less in the presence of water.
(31) The method for producing an xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound as described in (30) above, wherein the reaction is carried out at pH 8 or lower.
(32) The method for producing an xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound as described in (30) above, wherein water is 10 folds by weight or more based on the xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound.
(33) The method for producing an xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound as described in (30) above, wherein the reaction is carried out in an aqueous solution.
(34) The method for producing an xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound as described in (30) above, wherein the xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound of formula (VI) is xcex1,xcex1xe2x80x2-dichloro-o-xylene and the xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound of formula (VIII) is xcex1,xcex1xe2x80x2-dihydroxy-o-xylene.
Further, the present invention relates to the following production method for xcex1-halogeno-o-xylene compounds, production method for xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compounds, and production method for isochromanone compounds.
(35) A method for producing xcex1-halogeno-o-xylene compound from o-xylene compound by photohalogenation reaction under conditions of reduced pressure in gas phase at 50xc2x0 C. or higher and 300xc2x0 C. or lower, wherein conversion of o-xylene compound is controlled to 20% or higher and 50% or lower.
(36) The method for producing xcex1-halogeno-o-xylene compound as described in (35) above, wherein halogen or a mixed gas composed of halogen and inert gas is blown into liquid state o-xylene compound and the o-xylene compound is evaporated at a temperature of not higher than boiling point for use in the reaction.
(37) The method for producing xcex1-halogeno-o-xylene compound as described in (36) or (37) above, wherein the feed rate (mole/hour) of halogen to the feed rate of o-xylene compound is 0.1 or higher and 1.8 or lower.
(38) The method for producing xcex1-halogeno-o-xylene compound as described in any of (35) to (37) above, wherein after the reaction, unreacted o-xylene compound is recovered and reused.
(39) A method for producing xcex1-halogeno-o-xylene compound by reacting an o-xylene compound with halogen by radical reaction in liquid phase, wherein the conversion of o-xylene compound after the reaction is controlled in the range of 20% or higher and 70% or lower.
(40) The method for producing xcex1-halogeno-o-xylene compound as described in (39) above, wherein the o-xylene compound is diluted with an organic solvent and the reaction is carried out.
(41) The method for producing xcex1-halogeno-o-xylene compound as described in (39) or (40) above, wherein the reaction is carried out in the presence of a radical initiator or under irradiation of ultraviolet rays.
(42) The method for producing xcex1-halogeno-o-xylene compound as described in any of (39) to (41) above, wherein the reaction temperature is 50xc2x0 C. or higher and 150xc2x0 C. or lower.
(43) The method for producing xcex1-halogeno-o-xylene compound as described in any of (39) to (42) above, wherein the feed rate (mole/hour) of halogen to the feed rate of o-xylene compound is 0.1 or higher and 3 or lower.
(44) The method for producing xcex1-halogeno-o-xylene compound as described in any of (39) to (43) above, wherein the solvent used for reaction is at least one solvent selected from the group consisting of carbon tetrachloride, 1,2-dichloroethane, trichloroethane, benzene, chlorobenzene, fluorobenzene, and cyclohexane.
(45) The method for producing xcex1-halogeno-o-xylene compound as described in any of (39) to (44) above, wherein after the reaction, unreacted o-xylene compound is recovered and reused as a raw material.
(46) The method for producing xcex1-halogeno-o-xylene compound as described in any of (34) to (45) above, wherein the halogen is chlorine and the xcex1-halogeno-o-xylene compound is xcex1-chloro-o-xylene.
(47) A method for producing xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compound, comprising the step of:
hydrolyzing the xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (22) above at pH 11 or higher.
(48) The method for producing xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (47) above, wherein the xcex1-cyano -xcex1xe2x80x2-hydroxy-o-xylene compound obtained by the method described in any of (18) to (22) above is hydrolyzed.
(49) The method for producing xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compound as described in (47) or (48) above, wherein the xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound is xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene.
(50) A method for producing isochromanone compound, comprising the step of:
heating a metal salt of the xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compound obtained by the production method as described in (49) at pH 4 or lower.
The reaction scheme of the production method for isochromanone compound according to the present invention using an o-xylene compound as a raw material will be shown in Reaction Scheme 1 and Reaction Scheme 2 below. 
According to Reaction Scheme 1, the reaction starts from the o-xylene compound (I) to reach the isochromanone compound (V) through xcex1-halogeno-o-xylene compound (II), xcex1-cyano-o-xylene compound (III), and xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene compound (IV).
In the reaction according to Reaction Scheme 2, o-xylene compound (I) is converted through xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound (VI), xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compound (VII), and xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene compound (VIII) to xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound (IX). The resultant compound (IX) is derived (i) directly to isochoromanone compound (V) by hydrolysis with acid, or to (ii) alkali metal salt (X) of xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compound by alkali hydrolysis and then this is subjected to intramolecular esterification reaction to derive it to isochromanone compound (V).
Hereinafter, the reactions according to Reaction Schemes 1 and 2, respectively, will be explained in order of steps.
Step 1: Production Method for xcex1-halogeno-o-xylene Compound (Preparation of compound of formula (II) from compound of formula (I))
The raw material to be used, o-xylenes, are represented by formula (I) 
In the formula, R1 and R2 independently of each other represent hydrogen atom or an alkyl group, R3 represents hydrogen atom, halogen atom, an alkoxy group, a hydroxyalkyl group having 2 or more carbon atoms, or a carboxyl group, and n is an integer of 0 to 4, provided that when n is 2 or more, (R3)s may be the same or different.
Hereinafter, taking the case of xcex1-chlorination of o-xylene which is an inexpensively available industrial material as a specific example of compounds of formula (I), production methods in gas phase and liquid phase that can give xcex1-chloro-o-xylene with high selectivity will be explained.
Reaction in Gas Phase
In the present step, the reaction method in gas phase is carried out by heating o-xylene as a raw material to vaporize, continuously introducing the resultant gas together with chlorine gas to a reactor. While irradiating ultraviolet rays to the mixed gas composed of o-xylene and chlorine, the reaction is carried out. The mixed gas containing xcex1-chloro-o-xylene after the reaction is discharged from the reactor and is cooled in a heat exchanger to obtain a liquefied reaction product. This is sampled, analyzed and the conversion (%) of o-xylene is obtained by the following equation (1).                     Conversion        =                  xe2x80x83                ⁢                                            {                        ⁢                          (                        ⁢            mol            ⁢                          xe2x80x83                        ⁢            of            ⁢                          xe2x80x83                        ⁢            o            ⁢                          -                        ⁢            xylene            ⁢                          xe2x80x83                        ⁢            before            ⁢                          xe2x80x83                        ⁢            the            ⁢                          xe2x80x83                        ⁢            reaction                    -                                                  xe2x80x83                ⁢                  mol          ⁢                      xe2x80x83                    ⁢          of          ⁢                      xe2x80x83                    ⁢          o          ⁢                      -                    ⁢          xylene          ⁢                      xe2x80x83                    ⁢          after          ⁢                      xe2x80x83                    ⁢          the          ⁢                      xe2x80x83                    ⁢          reaction          ⁢                                    )                        ÷                          ⁢                  xe2x80x83                                                  xe2x80x83                ⁢                              (                    ⁢          mol          ⁢                      xe2x80x83                    ⁢          of          ⁢                      xe2x80x83                    ⁢          o          ⁢                      -                    ⁢          xylene          ⁢                      xe2x80x83                    ⁢          before          ⁢                      xe2x80x83                    ⁢          the          ⁢                      xe2x80x83                    ⁢          reaction          ⁢                      )                    ⁢                      }                    xc3x97          100                    
In the method of the present step, the feed rate of raw material, the ratio of o-xylene to chlorine and/or reaction temperature are adjusted such that the above conversion of o-xylene is in the range of 20% or higher and 50% or lower.
The reaction in the present step may be at atmospheric pressure or under reduced pressure. When the reaction is too vigorous, reaction may be carried out after the reaction mixture is diluted with inert gas that gives no influence to the reaction, such as argon or nitrogen.
The vaporization of raw material, o-xylene, may be carried out only by heating or by blowing gas such as chlorine gas or inert gas into o-xylene liquid to vaporize it. When the reaction temperature is set at low temperatures, or it is desired to vaporize o-xylene at low temperatures, the method of blowing gas into liquid o-xylene is preferred. Also, o-xylene may be vaporized at temperatures below its boiling point by placing it under reduced pressure.
In the reaction of the present invention, the conversion of o-xylene below 20% is undesirable since productivity is low. On the other hand, the conversion of o-xylene above 50% is undesirable since perchlorinated products such as xcex1,xcex1xe2x80x2-dichloro-o-xylene increase so that the selectivity of xcex1-chloro-o-xylene is decreased. Here, selectivity (%) is defined by the following equation (2):
xe2x80x83Selectivity={(mol of xcex1-chloro-o-xylene after the reaction)÷(mol of consumed o-xylene)}xc3x97100xe2x80x83xe2x80x83(2)
The o-xylene contained in the reaction product unreacted without being converted into xcex1-chloro-o-xylene can be recovered by distilling the reaction product and reused as a raw material for producing xcex1-chloro-o-xylene.
The feed rate (mole/hour) of chlorine gas to the feed rate (mole/hour) of o-xylene to be fed is preferably in the range of 0.1 to 4.0. The ratio of chlorine of 4 or higher is undesirable since the amount of chlorine remaining unreacted in the gas after the reaction increases.
Reaction in Liquid Phase
The reaction method in liquid phase is carried out by charging o-xylene or o-xylene diluted with a solvent in a reactor, adding a radical initiator such as azobisisobutyronitrile (AIBN) or by irradiating ultraviolet rays to the reaction solution while blowing chlorine gas. The reaction mixture is sampled and unreacted o-xylene is analyzed. The conversion of o-xylene is obtained by the equation (1) above.
When the conversion of o-xylene reached in the range of 20 to 70%, the blowing of chlorine gas is stopped to terminate the reaction.
The radical initiator used in the present invention may be any one that is generally used usually as radical initiator. Azobis compounds such as AIBN, peroxides such as t-butyl peroxide and benzoyl peroxide, phenylazotriphenylmethane, etc. are used preferably.
The reaction in liquid phase may be run without solvents. When solvents are used, it is advantageous to dilute o-xylene in a concentration by weight of 5 to 80% before it is reacted. If the concentration of o-xylene is lower than 5%, a large amount of solvent is to be used and the concentration of product is low, resulting in low productivity. If the concentration of o-xylene is higher than 80%, perchlorinated products such as xcex1,xcex1xe2x80x2-dichloro-o-xylene are produced to lower not only the selectivity but also yield of the target xcex1-chloro-o-xylene. Here, the selectivity of xcex1-chloro-o-xylene is obtained by the above equation (2).
Generally, the solvent is not particularly limited so far as it does not adversely affect radical substitution reaction. For example, halogenated carbon solvents (carbon tetrachloride, dichloromethane, chloroform, dichloroethane, trichloroethane, hexachloroethane, perfluorohexane, perfluorocyclohexane), hydrocarbon solvents (cyclohexane, hexane), aromatic solvents (benzene, fluorobenzenes, chlorobenzenes, trifluoromethylbenzenes, trichloromethylbenzenes), etc. can be used.
The reaction is terminated when the conversion of o-xylene falls in the range of 20 to 70%. The conversion of xylenes of below 20% is undesirable since productivity is low although the selectivity of xcex1-chloro-o-xylene is high. The conversion of o-xylene above 70% is undesirable since perchlorinated products such as xcex1,xcex1xe2x80x2-dichloro-o-xylene increase to lower the selectivity of xcex1-chloro-o-xylene.
After completion of the reaction, the raw material o-xylene which remains in the reaction product unreacted without being chlorinated can be recovered by distillation, etc. and reused as a raw material for the production of xcex1-chloro-o-xylene.
In the present invention, the feed rate (mol/hour) of chlorine to that of o-xylene to be fed is preferably 0.1 to 3. The ratio of chlorine of below 0.1 is undesirable since it makes the reaction to take a longer time. The ratio of above 3 is also undesirable since the amount of chlorine gas discharged in an unreacted state to the outside the system increases.
The xcex1-chloro-o-xylene produced in the present reaction can give xcex1-chloro-o-xylene containing less impurities such as xcex1,xcex1xe2x80x2-dichloro-o-xylene merely by heating the reaction mixture after the completion of reaction at atmospheric pressure or under reduced pressure to distill off the solvent and unreacted o-xylene to concentrate. If a further purified xcex1-chloro-o-xylene is desired, it can be purified by distillation, etc.
Step 2: Production Method for xcex1-cyano-o-xylene Compound (Preparation of compound of formula (III) from compound of formula (II))
By reaction of an xcex1-halogeno-o-xylene compound of formula (II) 
(wherein R1 and R2 independently of each other represent hydrogen atom or an alkyl group, R3 represents hydrogen atom, halogen atom, an alkoxy group, a hydroxyalkyl group having 2 or more carbon atoms, or a carboxyl group, and n is an integer of 0 to 4, provided that when n is 2 or more, (R3)s may be the same or different) with a cyanidating agent such as sodium cyanide, an xcex1-cyano-o-xylene compound of formula (III) 
(wherein the symbols have the same meanings as defined above) can be synthesized.
That is, the production method of xcex1-cyano-o-xylene compound (II) is carried out by adding 1 equivalent or more of an aqueous sodium cyanide solution to an xcex1-halogeno-o-xylene compound in the presence of a phase transfer catalyst such as tetrabutylammonium bromide and heating with stirring to perform the reaction. The reaction mixture is separated into two layers and the organic layer is recovered. Then, to remove moisture in the organic layer, a drying agent such as calcium chloride is used or water is distilled off to obtain xcex1-cyano-o-xylenes which can be used as a raw material for the production in the present invention.
Step 3: Production Method for xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene Compound (Preparation of compound of formula (IV) from compound of formula (III))
By reaction of the xcex1-cyano-o-xylene compound of formula (III) obtained in the above Step 2 with halogen xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes of formula (IV) 
(wherein R1, R2, and R3 have the same meanings as defined above and X represents a halogen atom) can be produced.
When the reaction is carried out in liquid phase, an xcex1-cyano-o-xylene in a liquid state or diluted with a solvent is charged in a reactor and halogen gas is blown into the liquid for reaction in the presence of a radical initiator such as AIBN or under the condition of irradiation with ultraviolet rays. The radical initiator includes besides AIBN t-butyl peroxide, benzoyl peroxide, phenylazotriphenylmethane, etc. However, it is not particularly limited and any one may be used so far as it serves as a radical initiator. In this case, solvents may or need not be used. Preferably, xcex1-cyano-o-xylene is diluted in a concentration by weight of 5 to 80% before it is reacted. If the concentration of xcex1-cyano-o-xylene is lower than 5%, productivity is too low for an industrial process. If the concentration of xcex1-cyano-o-xylene is higher than 80%, the selectivity of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes becomes lower resulting in low yield of the target compound. Generally, the solvent is not particularly limited so far as it does not adversely affect radical substitution reaction by halogen. For example, carbon tetrachloride, dichloroethane (EDC), etc. can be used. Also, production of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes is possible by gas phase reaction. In this case, xcex1-cyano-o-xylenes are heated and vaporized and reacted with halogen gas under irradiation of ultraviolet rays to produce xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes. The reaction system may be any of under pressure, under atmospheric pressure, or under reduced pressure, so far as the reaction mixture can exist in gaseous state. Usually, the reaction is carried out under atmospheric pressure or under reduced pressure. Also, it is possible to carry out the synthesis by diluting the reaction system with gas that does not adversely affect the reaction, such as argon or nitrogen.
The above reaction, no matter whether it is liquid phase reaction or gas phase reaction, is carry out preferably at a conversion (%), as defined by the following equation (3), of the raw material xcex1-cyano-o-xylenes being controlled to 10 to 80%.                                                         Conversion              =                              xe2x80x83                            ⁢                                                {                                ⁢                                  (                                ⁢                α                ⁢                                  -                                ⁢                cyano                ⁢                                  -                                ⁢                o                ⁢                                  -                                ⁢                xylene                ⁢                                  xe2x80x83                                ⁢                before                ⁢                                  xe2x80x83                                ⁢                and                ⁢                                  xe2x80x83                                ⁢                after                                                                                                        xe2x80x83                            ⁢                              the                ⁢                                  xe2x80x83                                ⁢                reaction                ⁢                                  xe2x80x83                                ⁢                                  (                                ⁢                mol                ⁢                                  xe2x80x83                                ⁢                %                ⁢                                  xe2x80x83                                ⁢                difference                ⁢                                  )                                ⁢                                                      )                                    ÷                                                                                                                        xe2x80x83                            ⁢                                                (                                ⁢                α                ⁢                                  -                                ⁢                cyano                ⁢                                  -                                ⁢                o                ⁢                                  -                                ⁢                xylene                ⁢                                  xe2x80x83                                ⁢                before                ⁢                                  xe2x80x83                                ⁢                the                ⁢                                  xe2x80x83                                ⁢                reaction                                                                                                        xe2x80x83                            ⁢                                                (                                ⁢                mol                ⁢                                  xe2x80x83                                ⁢                %                ⁢                                  )                                ⁢                                  )                                ⁢                                  }                                xc3x97                100                                                                        (        3        )            
If the conversion of xcex1-cyano-o-xylenes is lower than 10%, the productivity is low while the conversion of xcex1-cyano-o-xylenes is higher than 80%, production of dihalogeno form, etc. by-products increases, resulting in that the selectivity (%) of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes as defined by the following equation (4) is decreased.                                                         Selectivity              =                              xe2x80x83                            ⁢                                                {                                ⁢                                  (                                ⁢                α                ⁢                                  -                                ⁢                halogeno                ⁢                                  -                                ⁢                                  α                  xe2x80x2                                ⁢                                  -                                ⁢                cyano                ⁢                                  -                                ⁢                o                ⁢                                  -                                ⁢                xylene                ⁢                                  xe2x80x83                                ⁢                                  (                                      mol                    ⁢                                          xe2x80x83                                        ⁢                    %                                    )                                ⁢                                                      )                                    ÷                                                                                                                        xe2x80x83                            ⁢                                                (                                ⁢                α                ⁢                                  -                                ⁢                cyano                ⁢                                  -                                ⁢                o                ⁢                                  -                                ⁢                xylene                ⁢                                  xe2x80x83                                ⁢                                  (                                      mol                    ⁢                                          xe2x80x83                                        ⁢                    %                    ⁢                                          xe2x80x83                                        ⁢                    difference                    ⁢                                          xe2x80x83                                        ⁢                    between                                                                                                                                                                                                      xe2x80x83                                        ⁢                                          before                      ⁢                                              xe2x80x83                                            ⁢                      and                      ⁢                                              xe2x80x83                                            ⁢                      after                      ⁢                                              xe2x80x83                                            ⁢                      reaction                                        )                                    )                                }                            xc3x97              100                                                          (        4        )            
After the reaction, the raw material xcex1-cyano-o-xylenes remaining unreacted in the system can be recovered and reused. Although the reaction mixture may be used as it is, it may be purified to a suitable purity by distillation, etc., if desired, before it is used in the reaction.
Step 4: Production Method for Isochromanones by Hydrolysis of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene Compound (Preparation of compound of formula (V) from compound of formula (IV))
By heating and hydrolyzing the xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes of formula (IV) obtained in the above Step 3 in water or water containing a protic polar solvent, isochromanone compound of formula (V) 
(wherein the symbols have the same meanings as defined above) can be produced.
As a raw material for the production of isochromanones, usually chlorinated form is used among xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes since it is advantageous in view of cost. xcex1-Chloro-xcex1xe2x80x2-cyano-o-xylene can be produced according to the above Step 3. Besides, one produced by reacting xcex1-cyano-o-xylene with sulfuryl chloride by a known method and purified by distillation or crystallization can be used.
As the solvent, water alone is operable. However, it is possible to add protic polar solvents such as lower alcohols (for example, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, and butanol). The protic polar solvents are used in order to increase the affinity of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes for water and carry out hydrolysis reaction more efficiently. When water containing a lower alcohol is used as a solvent, it is necessary to adjust the concentration of alcohol, reaction conditions, etc. since alcohol when in high concentration may cause side reactions with xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes.
The amount of water used as a solvent is 1 fold by weight or more and 10 fold by weight or less, preferably 1 fold by weight or more and 5 folds by weight or less, based on the weight of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes. The amount of 1 fold by weight or more and 5 folds by weight or less is industrially advantageous from the point of view of the conversion of xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes into isochromanones or productivity of isochromanones based on the amount of solvents used.
To improve productivity, it is advantageous to add to the reaction mixture an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid and/or Lewis acids, e.g., metal chlorides such as aluminum chloride and zinc chloride, particularly preferably hydrochloric acid in an amount of 0.1 equivalent or more and 5 equivalents or less, preferably 0.3 equivalents or more and 3.5 equivalents or less, based on xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes.
The reaction temperature is advantageously 70 to 200xc2x0 C., preferably 100 to 150xc2x0 C.
Further, if necessary, the reaction can be carried out under pressure. On this occasion, it is advantageous that the pressure condition is higher than atmospheric pressure and 20 kg/cm2 or less, preferably 0.5 kg/cm2 or higher and 7 kg/cm2 or lower.
The present reaction proceeds usually as two layer reaction or in a state of suspension so that yield can be increased by improving the state of mixing by enhancement of stirring apparatus and so on.
Recovery of isochromanones after the reaction is possible by concentration of reaction mixture or extraction with organic solvents such as ethyl acetate, methylene chloride, toluene, xylene, and ethylbenzene. Depending on the target isochromanones, when there are two layers, i.e., water layer and product layer, it is possible to separate the water layer and remove it. In particular, when the product is 3-isochromanone, the product layer is liquid at 85xc2x0 C. or higher, and the solubility in water is low so that the target compound can be recovered by the operation of separation. Further, it is possible to obtain high purity 3-isochromanone by distillation purification under reduced pressure.
Thus, isochromanones can be produced in high yield and at high purity by using xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylenes as a raw material in an industrially advantageous manner at low cost, by easy operation and with producing less wastes.
Step 5: Production Method for xcex1,xcex1xe2x80x2-dihalogeno-o-xylene Compounds (Preparation of compound of formula (VI) from compound of formula (I))
The raw material o-xylene compound to be used is represented by formula (I) 
(wherein, R1 and R2 independently of each other represent hydrogen atom or an alkyl group, R3 represents hydrogen atom, halogen atom, an alkoxy group, a hydroxyalkyl group having 2 or more carbon atoms, or a carboxyl group, and n is an integer of 0 to 4, provided that when n is 2 or more, (R3)s may be the same or different).
Halogenation of the compound of formula (I) using a photocatalyst or radical initiator can give rise to an xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound of formula (VI) 
(wherein R1, R2, and R3 have the same meanings as defined above and X represents a halogen atom).
For example, o-xylene is chlorinated with chlorine using a photocatalyst or radical initiator and purified by distillation to obtain xcex1,xcex1xe2x80x2-dichloro-o-xylene (Chem. Technik, 20, 38 (1968)).
Step 6: Production Method for xcex1,xcex1xe2x80x2-dihydroxy-o-xylene Compounds (Preparation of compound of formula (VII) from compound of formula (VI))
Using xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes of formula (VI) explained in Step 5, the production method for xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compounds of formula (VII) 
(the symbols in the formula have the same meanings as defined above) will be explained.
Preferred examples of R1 and R2 in formula (VI) include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, etc. Particularly preferred is a hydrogen atom.
(R3)s, which may be the same or different, each represent a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methoxy group, an ethoxy group, etc. The case where all (R3)s are hydrogen atoms is particularly preferable.
X is, for example, an iodine atom, a bromine atom, or a chlorine atom. From the point of view of cost, a chlorine atom is particularly preferable.
As a specific example of xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes, particularly xcex1,xcex1xe2x80x2-dichloro-o-xylene is preferred.
According to the method of the present step, xcex1,xcex1xe2x80x2-dihydroxy-o-xylene compounds can be prepared by heating xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compounds in the presence of water at pH 8 or lower.
The reaction solvent is preferably water. However, non-polar solvents such as toluene and xylene, polar solvents such as dimethylformamide, dimethyl sulfoxide, and dioxane, and the like general organic solvents may be added. Use of non-polar solvents can prevent production of dimers. Also, use of polar solvents can reduce water. However, alcohols such as methanol and ethanol which react with xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes forming an ether bond and those which are readily hydrolyzed, such as ethyl acetate, are not desirable.
The amount of water to be added to xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes is suitably 10 folds by weight or more. The upper limit is not particularly limited but 20 folds by weight or lower, further 13 to 18 folds by weight, is preferred. When the addition amount is too small, the conversion of xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes is not increased while it is too high, problems in productivity occur such as removal of water. However, when the reaction is carried out by addition of organic solvents to water, sometimes the addition amount of water as described above can be reduced. For example, use of water to which dimethylformamide or dimethyl sulfoxide is added can reduce the addition amount of water to from 2 folds by weight to 10 folds by weight based on xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes.
The reaction temperature is 50 to 130xc2x0 C., preferably 80 to 110xc2x0 C. At low temperatures, the reaction proceeds slowly and hence productivity is low. At high temperatures, high-pressure reactor or high temperature thermal medium is necessary, which is industrially disadvantageous.
According as the reaction proceeds, hydrogen halides are generated. If the reaction is continued for many hours in a state where hydrogen halide is at high concentrations, xcex1-chloro-xcex1xe2x80x2-hydroxy form, intermediate, generates condensates as a result of intermolecular dehydrohalogenation, resulting in a decrease in yield. Therefore, it is preferred that the reaction time be selected taking into consideration the conversion of xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes in the system.
The reaction may be carried out while neutralizing the hydrogen halide that is generated during the reaction. However, in this case, at pH 9 or higher, the xcex1-chloro-xcex1xe2x80x2-hydroxy form, intermediate, undergoes intramolecular dehydrohalogenation to produce phthalans of formula (XI) described above to lower yield of xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes, so that pH must be 8 or lower.
The raw material xcex1,xcex1xe2x80x2-dihalogeno-o-xylene compound of formula (VI) has low solubility in water depending on the kinds of its substituents R1 to R3 and even in the reaction which proceeds in systems containing much water, it is sometimes the case that the reaction mixture is in a state separated into two layers. In this case, production of the above-described intermolecular condensates is promoted to decrease yield. This does not depend on the kind of raw materials and when the addition amount of water is small, the reaction mixture is separated into two layers and similar results are obtained. In such case, production of intermolecular condensates can be prevented by addition of organic solvents to lower the concentration of reactants in the organic layer.
As the target xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes (VII), the reaction mixture may be used in the next step as it is without isolation. If necessary, water may be evaporated to concentrate the reaction mixture before use. It is advantageous to carry out concentration operation at 20 to 60xc2x0 C., preferably 30 to 50xc2x0 C. When the temperature is too low, the concentration takes a long time whereas when the temperature is too high, production of condensates is promoted, so that both cases are industrially disadvantageous. When pH is too high, phthalan compounds are produced upon concentration to cause loss of xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes, so that concentration may be advantageously conducted after adjusting pH in the neutral regions not exceeding 9, preferably 8, with an alkali agent.
Thus, heating xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes in the presence of water at pH 8 or lower can produce corresponding xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes in an industrially advantageous manner in view of cost and operation. Particularly preferred examples of xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes is xcex1,xcex1xe2x80x2-dihydroxy-o-xylene.
Step 7: Production Method for xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene Compounds (Preparation of compound of formula (VIII) from compound of formula (VII))
Production method for xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes of formula (VIII) 
(the symbols in the formula have the same meanings as defined above) characterized by reacting xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes of formula (VII) with a hydrogen halide will be explained.
Preferred examples of R1 and R2 in formula (VII) include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, etc. Particularly preferred is a hydrogen atom.
Preferred examples of R3 include a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methoxy group, an ethoxy group, etc. The case where all (R3)s are hydrogen atoms is particularly preferable.
xcex1-Halogeno-xcex1xe2x80x2-hydroxy-o-xylene, which is a raw material for the synthesis of 3-isochromanone, can be produced in high yields by the method of the present step.
xcex1,xcex1xe2x80x2-Dihydroxy-o-xylenes of formula (VII), raw materials, can be produced by the method of the Step 6 according to the present invention. However, those produced by other known methods may also be used.
The solvent when xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes are reacted with a hydrogen halide may be organic solvents or water. In the case of organic solvents, there can be used hydrophobic solvents such as toluene and xylene and polar solvents such as dimethylformamide, dimethyl sulfoxide, and dioxane. Industrially, water is advantageous taking into consideration recovery of solvents, danger upon use, etc. Water and organic solvents can be used in combination. It is particularly preferred that water and hydrophobic organic solvents be used in combination.
The charge concentration of xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes is not particularly limited. However, if it is too low, problem occurs on productivity. As hydrogen halide to be reacted is used preferably hydrogen chloride, which is less expensive. Usage of 0.5 to 3 folds by mole based on xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes is suitable and preferably 1.0 to 2.5 folds by mole. This usage may vary depending on the solvent, reaction temperature and reaction time used. At low molar ratio, the conversion is not increased while at high molar ratio, production of xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes occurs to decrease yield. As for the method of adding hydrogen halide, it may be added en bloc at the initiation of reaction or it may be added continuously. The method of addition may be by blowing dry gas or solutions in water or organic solvents may be used. The concentration of hydrogen halide in the reaction mixture is advantageously 5 to 30%. If the concentration is low, the conversion is decreased while if it is high, high boiling materials are produced as a result of intermolecular dehydrocondensation or dehydrohalogenation condensation between xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes and xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes, thereby decreasing yield.
The reaction temperature is preferably 80 to 100xc2x0 C. If it is too low, a decrease in conversion occurs while if it is too high, production of high boiling materials similarly causes a decrease in yield and both cases are undesirable.
The reaction time is determined considering change in products. Lowering temperature or increasing pH to near neutral region with an alkali agent can terminate the reaction. Equilibrium may vary depending on conditions and it is desirable to select various conditions so that xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes can be obtained in high yields. By-produced xcex1,xcex1xe2x80x2-dihalogeno-o-xylenes similarly undergoes xcex1,xcex1xe2x80x2-dicyanidation in case the reaction proceeds to the step of xcex1-cyanidating xcex1-halogen, so that it is necessary to inhibit the generation thereof as much as possible.
The reaction style of Step 7 may be batch-wise or continuous.
Although explanation has been made on xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes as above, the reaction of Step 7 can be applied to m-xylene compounds and p-xylene compounds. xcex1-Halogeno-xcex1xe2x80x2-hydroxy-m-xylenes can be produced from xcex1,xcex1xe2x80x2-dihydroxy-m-xylenes. Also, xcex1-halogeno-xcex1xe2x80x2-hydroxy-p-xylenes can be produced from xcex1,xcex1xe2x80x2-dihydroxy-p-xylenes. Preferred example of the former is xcex1-chloro-xcex1xe2x80x2-hydroxy-m-xylene and preferred example of the latter is xcex1-chloro-xcex1xe2x80x2-hydroxy-p-xylene.
Step 8: Production Method for xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene Compounds (Preparation of compound of formula (IX) from compound of formula (VIII))
Reacting xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes of formula (VIII) with hydrogen cyanide or salts thereof can produce xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes of formula (IX) 
(the symbols in the formula have the same meanings as defined above).
Preferred examples of R1 and R2 in formula (VIII) include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, etc. Particularly preferred is a hydrogen atom. Preferred examples of R3 include a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methoxy group, an ethoxy group, etc. The case where all (R3)s are hydrogen atoms is particularly preferable.
xcex1-Cyano-xcex1xe2x80x2-hydroxy-o-xylene, which is a raw material for the synthesis of 3-isochromanone, can be produced in high yields by the method of the present step.
xcex1-Halogeno-xcex1xe2x80x2-hydroxy-o-xylenes, raw materials, can be produced by the method of the Step 7 according to the present invention. However, those produced by other known methods may also be used.
When the xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes obtained by the method of Step 7 above are used as raw materials, the reaction mixture of Step 7 may be used as it is or it may be concentrated and cooled to separate and collect xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes as solids content before use. Industrially, it is preferred to use the reaction mixture as it is in view of reduction of production steps. Although organic solvents may be added freshly, this is industrially disadvantageous since recover operation and the like are cumbersome. When the reaction mixture of xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes is used as it is, it is separated into an oil layer in which main component is xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes and a water layer which contains xcex1,xcex1xe2x80x2-dihydroxy-o-xylenes, raw material, and some xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes. Therefore, addition of a phase transfer catalyst is more efficient in order to perform cyanidation in a stable manner and in high yield. The phase transfer catalyst may be any of generally used ones. For example, addition of tetrabutylammonium bromide in an amount of 1 to 20% by weight, preferably 3 to 10% by weight, based on xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes before the reaction is started increases reactivity of cyanidation.
As the cyanidating agent, hydrocyanic acid (prussic acid) or its salts may be used. Industrially used sodium cyanide is preferable since it is economical. Usually, an aqueous solution of it is used. Upon initiation of the reaction, it is preferred that the pH at which cyanidation reaction is practiced be adjusted with an alkali agent such as caustic alkali in advance. The pH in the cyanidation reaction is suitably 5 to 13, preferably 6 to 9. If pH is low, the reaction proceeds slowly and hydrogen cyanide gasifies to decrease rate of reaction, which is industrially disadvantageous. If the pH is high, the portion once halogenated is hydrolyzed again to decrease yield. In addition, dehydrohalogenation occurs in the molecule to produce phthalan compound to decrease yield. Upon cyanidation, when hydrogen cyanide is used as a cyanidating agent, it is desirable that the liquid is dropped or gas is fed into the liquid while controlling the pH with an alkali agent. When salts of hydrogen cyanide, for example, sodium cyanide is used, pH increases so that it is desirable that dropping is carried out while adjusting the pH of the reaction mixture with mineral acid, for example, hydrochloric acid or sulfuric acid.
The reaction temperature is 50 to 120xc2x0 C., preferably 70 to 100xc2x0 C. If it is too low, the reactivity is decreased and if it is too high, yield is decreased. The reaction time may vary depending on the reaction temperature and may be determined taking into consideration the conversion of xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylenes.
The reaction style of Step 8 may be batch-wise or continuous.
Although explanation has been made on xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes as above, the reaction of Step 8 can be applied to m-xylene compounds and p-xylene compounds. xcex1-Cyano-xcex1xe2x80x2-hydroxy-m-xylenes can be produced from xcex1-halogeno-xcex1xe2x80x2-hydroxy-m-xylenes. Also, xcex1-cyano-xcex1xe2x80x2-hydroxy-p-xylenes can be produced from xcex1-halogeno-xcex1xe2x80x2-hydroxy-p-xylenes. Preferred example of the former is xcex1-cyano-xcex1xe2x80x2-hydroxy-m-xylene and preferred example of the latter is xcex1-cyano-xcex1xe2x80x2-hydroxy-p-xylene.
Step 9: Production Method for Isochromanones by Acid Hydrolysis of xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene Compounds (Preparation of compound of formula (V) from compound of formula (IX))
Acid hydrolysis of xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compounds of formula (IX) can produce isochromanone compounds of formula (V) 
(the symbols in the formula have the same meanings as defined above).
Preferred examples of R1 and R2 in formula (V) include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, etc. Particularly preferred is a hydrogen atom. Preferred examples of R3 include a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methoxy group, an ethoxy group, etc. The case where all R3 is a hydrogen atom is particularly preferable. Preferred example of isochromanones includes 3-isochromanone.
xcex1-Cyano-xcex1xe2x80x2-hydroxy-o-xylenes of formula (IX), raw materials, can be produced by the method of the Step 8 above. However, production method is not limited particularly and those produced by other known methods may also be used.
The hydrolysis with acid in this step can be carried out by adding mineral acid such as sulfuric acid or hydrochloric acid to the cyanidation reaction completed liquid in the Step 8 above and heating the mixture. Sulfuric acid is preferred from the viewpoint of apparatus and costs and is advantageously added 1 to 3 folds by mole, preferably 1.8 to 2.3 folds by mole, based on xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes. If the molar ratio is low, the conversion of xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes is decreased and if it is high, such is industrially disadvantageous.
After the reaction, recovery of isochromanones can be carried out by concentration of reaction mixture or extraction with an organic solvent such as ethyl acetate, toluene, xylene, ethylbenzene, or methylene chloride. When the reaction mixture is separated into two layers, i.e., a water layer and a product layer, depending on the target isochromanones, it is possible to separate and remove the water layer. In particular, when the product is 3-isochromanone, the product layer is liquid at 85xc2x0 C. or higher, so that solubility in water is low and the target compound can be recovered by separation operation. Further, distillation and purification under reduced pressure can give rise to highly pure 3-isochromanone.
Step 10: Production Method for xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene Compounds (Preparation of compound of formula (X) from compound of formula (IX))
Hydrolysis of xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (IX) under an alkaline condition at pH 11 or higher can produce xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylenes of formula (X) 
(wherein R1, R2, and R3 have the same meanings as defined above and M represents an alkali metal).
Preferred examples of R1 and R2 in formula (X) include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, etc. Particularly preferred is a hydrogen atom. Preferred examples of R3 include a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methoxy group an ethoxy group, etc. The case where all (R3)s are hydrogen atoms is particularly preferable. Examples of M include sodium, potassium, etc.
By the production method in the present step, xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylenes, raw material for the synthesis of 3-isochromanone can be produced in high yields.
Preferred examples of R1 and R2 in formula (IX) include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, etc. Particularly preferred is a hydrogen atom. Preferred examples of R3 include a hydrogen atom, a chlorine atom, a fluorine atom, a bromine atom, a methoxy group, an ethoxy group, etc. The case where all (R3)s are hydrogen atoms is particularly preferable.
xcex1-Cyano-xcex1xe2x80x2-hydroxy-o-xylenes, raw materials, can be produced by the method of the Step 8 above. However, production method is not limited particularly and those produced by other known methods may of course be used.
When the xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes produced by the method of Step 8 above are used as raw materials, they are hydrolyzed under an alkaline condition to synthesize xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylenes or salts thereof. It is industrially advantageous to use the reaction mixture as it is. When a reduction in volume is desired, particularly when the reaction is carried out in aqueous systems, the completed reaction mixture was left to stand and the water layer is discarded and then the layer of xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes is sent to the hydrolysis step. The hydrolysis reaction stoichiometrically requires at least 2 moles of water based on xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes, preferably 3 moles or more.
The hydrolysis at alkali regions is carried out using ammonia or amines as a catalyst. However, industrially, caustic soda is preferred also from the viewpoint of cost. Concentration of alkali is adjusted such that it is always 0.3 to 1.5% by weight in a free state in the system or 1.0 to 1.3 folds by mole of alkali based on xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylenes is added en bloc before the reaction is carried out. During the reaction, ammonia gas that is generated is neutralized and detoxicated with acid such as sulfuric acid. As for the reaction time, the reaction may be carried out until no ammonia is generated. The reaction may be continued until the conversion reaches saturation while analyzing by HPLC, etc. After completion of the reaction, xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylenes exist as alkali salts in the reaction mixture.
xcex1-Carboxy-xcex1xe2x80x2-hydroxy-o-xylenes in alkali regions at pH 9 or higher undergoes dehydrogenodehalogenation within the molecule to by-produce phlathan compounds to decrease yield. Strict control of pH such as maintaining it to preferably pH 6 to 8 is necessary.
Although explanation has been made on xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylenes as above, the reaction of Step 10 can be applied to m-xylene compounds and p-xylene compounds. xcex1-Carboxy-xcex1xe2x80x2-hydroxy-m-xylenes can be produced from xcex1-cyano-xcex1xe2x80x2-hydroxy-m-xylenes. Also, xcex1-carboxy-xcex1xe2x80x2-hydroxy-p-xylenes can be produced from xcex1-cyano-xcex1xe2x80x2-hydroxy-p-xylenes. Preferred example of the former is xcex1-carboxy-xcex1xe2x80x2-hydroxy-m-xylene and preferred example of the latter is xcex1-carboxy-xcex1xe2x80x2-hydroxy-p-xylene.
Step 11: Production Method for Isochromanones from Metal Salt of xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene Compounds (Preparation of compound of formula (V) from compound of formula (X))
Addition of an acid to an aqueous solution of a metal salt of xcex1-carboxy-xcex1xe2x80x2-hydroxy-o-xylene compound of formula (X) and hydrolysis at pH 4 or lower, preferably pH 3 or lower, and intramolecular dehydrocondensation can produce isochromanones.
After the reaction, recovery of isochromanones can be carried out by concentration of reaction mixture or extraction with an organic solvent such as ethyl acetate, toluene, xylene and ethylbenzene. When the reaction mixture is separated into two layers, i.e., a water layer and a product layer, depending on the target isochromanones, it is possible to separate and remove the water layer. In particular, when the product is 3-isochromanone, the product layer is liquid at 85xc2x0 C. or higher, so that solubility in water is low and the target compound can be recovered by separation operation. Further, distillation and purification under reduced pressure can give rise to highly pure 3-isochromanone.
According to the present invention, isochromanone compounds useful as raw materials for drugs and agricultural chemicals can be efficiently produced from o-xylene compounds which are industrially available at low costs (1) through xcex1-halogeno-o-xylene derivatives, xcex1-cyano-o-xylene derivatives and xcex1-halogeno-xcex1xe2x80x2-cyano-o-xylene derivatives, or (2) through xcex1,xcex1xe2x80x2-dihalogeno-o-xylene derivatives, xcex1,xcex1xe2x80x2-dihydroxy-o-xylene derivatives, and xcex1-cyano-xcex1xe2x80x2-hydroxy-o-xylene derivatives and xcex1-halogeno-xcex1xe2x80x2-hydroxy-o-xylene derivatives.
Further, according to the present invention, compounds, which are intermediates for the production of the isochromanone compounds and are useful as intermediates for other drugs and agricultural chemicals can be produced in an industrially advantageous manner.